ethynyl mida boronate: a readily accessible and highly versatile
TRANSCRIPT
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Tetrahedron 66 (2010) 4710e4718
Contents lists avai
Tetrahedron
journal homepage: www.elsevier .com/locate/ tet
Ethynyl MIDA boronate: a readily accessible and highly versatile building block forsmall molecule synthesis
Justin R. Struble, Suk Joong Lee, Martin D. Burke *
Howard Hughes Medical Institute, Roger Adams Laboratory, Department of Chemistry, University of Illinois at UrbanaeChampaign, Urbana, IL 61801, USA
a r t i c l e i n f o
Article history:Received 19 March 2010Received in revised form 1 April 2010Accepted 2 April 2010Available online 9 April 2010
Dedicated to Professor Brian Stoltz withcongratulations for his receipt of the Tetra-hedron Young Investigator Award
Keywords:MIDA boronatesIterative cross-couplingSmall molecule synthesisAlkynes Sonogashira couplingDielseAlder
* Corresponding author. E-mail address: burke@scs
0040-4020/$ e see front matter � 2010 Elsevier Ltd.doi:10.1016/j.tet.2010.04.020
a b s t r a c t
Ethynyl N-methyliminodiacetic acid (MIDA) boronate is a very useful building block for small moleculesynthesis. This compound can serve as both a bifunctional acetylene equivalent with the capacity forterminus-selective bis-functionalization and a versatile starting material for the preparation of a widerange of other MIDA boronate building blocks.
� 2010 Elsevier Ltd. All rights reserved.
1. Introduction
Many powerful strategies have been developed to advance thefacility with which small molecules can be prepared in the labo-ratory. Of these, that which is sometimes called ‘the building blockapproach’1 can be particularly enabling. In one idealized version ofthis strategy,2 a collection of pre-assembled building blocks havingall of the required functional groups pre-installed in the correctoxidations states and with the desired stereochemical relationshipsare brought together using only one stereospecific reaction in aniterative fashion. The inherent modularity of most small moleculenatural products and pharmaceuticals suggests that the theoreticalscope of this approach is substantial.
With the goal of maximally enabling such a strategy, we aredeveloping a platform of N-methyliminodiacetic acid (MIDA) boro-nate3 building blocks.2 MIDA boronates have a wide range offavorable chemical and physical properties that collectively renderthemhighly useful in this context. Specifically, these compounds areair-stable, monomeric, highly crystalline, free-flowing solids thatcan be stored indefinitely on the benchtop under air, are soluble inmany organic solvents, and are uniformly compatible with silica gelchromatography.2,4e8With respect to reactivity, theMIDA boronatefunctional group is inert toward cross-coupling under anhydrous
.uiuc.edu (M.D. Burke).
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conditions but can be readily hydrolyzed withmild aqueous base toyield a reactive boronic acid.4,5 This enables the iterative cross-coupling (ICC) of bifunctional MIDA boronates bearing a halide orpseudohalide. MIDA boronates are also stable to a wide range ofother common reaction conditions, making it possible to utilizemultistep synthesis pathways to prepare complex organoboranebuilding blocks from simple MIDA boronate starting materials.6,7 Inaddition, the in situ rate-controlled hydrolysis of MIDA boronates inthe presence of aqueous base can produce dramatic improvementsin the yields of cross-coupling reactions.8 This ‘slow-release’meth-odology has transformed even some of the most notoriouslyunstable boronic acids into air-stable and highly effective cross-coupling partners. Given the favorable features of this platform, thedevelopment of highly versatile MIDA boronate building blocksrepresents an important goal.
In this vein, ethynylMIDAboronate 1was very attractive. First, theethyne subunit appears in wide range of natural products, pharma-ceuticals, and materials. Thus, a simple, non-toxic, and air-stablebifunctional ethyne equivalent with the capacity for terminus-selec-tive bis-functionalization would be of substantial utility (Fig. 1A).Moreover, given the compatibility of MIDA boronates with manycommon reaction conditions6,7 and the considerable versatility of thealkyne functional group,we recognized that 1 could potentially serveas a very effective startingmaterial for the preparation ofmany othertypes of useful MIDA boronate building blocks (Fig. 1B).9
MeN
O
OB
O
O
MeN
O
OB
O
O
A
B
1
MeN
O
OB
O
O
MeN
O
OB
O
O
MeN
O
OB
O
O
MeN
O
OB
O
O
MeN
O
OB
O
O
MeN
O
OB
O
O
MeN
O
OB
O
O
1
Figure 1. A. Ethynyl MIDA boronate 1 is an air and chromatographically stable, highly crystalline solid that can serve as a bifunctional surrogate for acetylene. B. This compound alsorepresents a highly versatile starting material for the preparation of a range of other types of useful MIDA boronate building blocks.
J.R. Struble et al. / Tetrahedron 66 (2010) 4710e4718 4711
As part of our efforts to prepare a wide range of bifunctionalhaloalkenyl MIDA boronate building blocks for the stereospecificsynthesis of polyene motifs via ICC, we recently reported that 1 canbe prepared via the trimethylborate salt derived from reactingethynylmagnesium bromide 2 with trimethylborate (Scheme 1).10
We further discovered that running this MIDA transligationreaction at >115 �C11 can provide good yields of 1 on the decagramscale.10 Importantly, all of the reagents used in this synthesis areenvironmentally friendly and can be accessed on very large scale forvery low cost, including the MIDA ligand. Specifically, MIDA can beprepared on the kilogram scale from the commodity chemicalsiminodiacetic acid, formic acid, and formaldehyde.12,13 Iminodi-acetic acid is a starting material used to make herbicides (e.g.,Round-up�), environmental metal chelating reagents, and surfac-tants. As a result, tens of thousands of metric tons of iminodiaceticacid are produced annually14 and thismaterial is very inexpensive.15
MIDA is also biodegradable.16
Scheme 1. (Ref. 10).
Table 1
5 mol% Pd catalyst10 mol% CuIbase (3 equiv)
MeN
O
OB
O
O
1.15 equiv
NC Br
4a
MeN
OB ONC
Consistent with many other MIDA boronates that we haveprepared and studied, 1 is an air-stable, monomeric, highlycrystalline, free-flowing solid that is soluble in many commonorganic solvents and fully compatible with silica gel chromatog-raphy.10 We attribute the stability of this building block (in con-trast to the corresponding highly unstable boronic acid) to thepyramidalized and rigid MIDA boronate functional group lackinga reactive p-orbital on the boron atom4,6 (see Scheme 1 forcrystal structure). We herein describe the utility of 1 in both ICCand building block synthesis applications.
0.20 M in solvent23 °C, 3–6 h1.00 equiv
1 5a
O O
Entry Pd catalyst Base Solvent % Yield
1 Pd(PPh3)4 Piperidine THF 302 PdCl2(PPh3)2 ET3N THF 783 PdCl2(PPh3)2 ET3N DMSO 474 PdCl2(PPh3)2 ET3N CH3CN 595 PdCl2(PPh3)2 ET3N DMF 93
2. Results
The utility of 1 as a bifunctional acetylene equivalent with thecapacity for sequential, distinct derivitization of the two alkynetermini was first explored.17 There are a few prior reports ofSonogashira couplings with ethynyl boranes that proceed withspecialized substrates.18 As shown in Table 1, only low yields were
observed when 1 was coupled to 1-bromo-4-cyano benzene usingPd(PPh3)4 as catalyst and piperidine as base in THF (Table 1, entry1). Alternatively, switching to PdCl2(PPh3)2 and triethylamine led toa substantial improvement in yield (entry 2). A survey of solventsrevealed that while both DMSO and CH3CN led to inferior results(entries 3 and 4), an excellent isolated yield (93%) was observedwhen this reaction was performed in DMF (entry 5).
The scope of aryl halides amenable to Sonogashira couplingwith 1 under these standard conditions is very good. Specifically,as shown in Table 2, a series of electron-deficient aryl bromides4aeg (entries 1e7), electron neutral or rich aryl iodides 4iel(entries 9e12), as well as 2-heterocyclic bromides 4m and 4n(entries 13 and 14) all provided good to excellent yields of thedesired coupling products 5aem. Under these conditions, electronrich aryl bromides (e.g., 4h, entry 8) were competent electrophilesbut were less effective than the corresponding iodides (e.g., 4i,entry 9).
Table 2
MeN
O
OB
O
O
X
PdCl2(PPh3)2DMF, Et3N
MeN
O
OB
O
O
23 C, 4Š7 h1
4
5
Entry 4 5 Isolated yield (%)
1 BrNC
4a
MeN
O
OB
O
ONC
5a
93
2Br
NC
4b
MeN
O
OB
O
O
NC
5b
95
3Br
CN
4c
MeN
O
OB
O
O
CN
5c
92
4 BrF3C
4d
MeN
O
OB
O
OF3C
5d
69
5 Br
Me
O
4e
MeN
O
OB
O
O
Me
O
5e
80
6 BrO2N
4f
MeN
O
OB
O
OO2N
5f
65
7BrMe
O2N
4g
MeN
O
OB
O
OMe
O2N
5g
72
8 BrMeO
4h
MeN
O
OB
O
OMeO
5h
33
9 IMeO
4i
5h 80
10IMe
4j
MeN
O
OB
O
OMe
5i
75
11I
4k
MeMeN
O
OB
O
O
5j
Me
88
12I
4l
MeOMeN
O
OB
O
O
5k
MeO
88
13 S Br
4m
MeN
O
OB
O
O
S5l
67
14N
Br
4n
MeN
O
OB
O
O
N5m
55
MeN
O
OB
O
OMeO
NBr
Pd(OAc)2, SK3PO4 (excdioxane:H2O
60 °C, 6 86%
5h
4f
Scheme
J.R. Struble et al. / Tetrahedron 66 (2010) 4710e47184712
To complete the proposed sequential bis-functionalization of 1,we tested the capacity of alkynyl MIDA boronates to undergo cross-coupling with organohalides. SuzukieMiyaura couplings withalkynyl boronic acids are rare,19 presumably due to the instability ofthese intermediates. However, there are several reports with morestable alkynyl boronic esters,20 alkynyl(triisopropoxy)boratesalts,21,22 and trifluoroborate salts.23 We wanted to determinewhether it might be possible to achieve good yields in the cross-coupling of alkynyl boronic acids via employment of the corre-sponding alkynyl MIDA boronates such as 5j under ‘slow-release’cross-coupling conditions.8 Specifically, we have determined thatexposure of MIDA boronates to K3PO4 in organic solvent/watermixtures leads to a slow hydrolysis of the MIDA boronate over thecourse of several hours producing a constant supply of fresh boronicacid in the reaction mixture. If the rate of cross-coupling is fast rel-ative to the rate of boronic acid release, then the boronic acid israpidly consumed in a productive coupling reaction thereby avoid-ing its undesired in situ decomposition.
To test the hypothesis that alkynyl boronic acids could alsobenefit from this slow-release methodology, 5h and p-nitroben-zene were treated with Pd(OAc)2, SPhos, and aq K3PO4 in dioxane:H2O 5:1 at 60 �C for 6 h (Scheme 2), and an 86% isolated yield wasobserved. Thus, building block 1 has the potential to serve as a veryuseful bifunctional acetylene equivalent.
The utility of 1 as a versatile starting material for the prepara-tion of other MIDA boronate building blocks was also explored. Asdescribed above, in addition to being unreactive under a widerange of anhydrous cross-coupling conditions, the MIDA boronatefunctional group is stable to many common synthetic reagents.6,7,24
Previous reports have demonstrated that these reagents includeoxidants, reductants, soft nucleophiles, electrophiles, acids, anda wide range of anhydrous bases. Given these compatibilities andthe remarkable versatility of alkynes, we investigated whethera range of previously unexplored reactions could be performed onthe ethyne subunit of 1 while similarly leaving the MIDA boronatefunctional group intact.
As shown in Scheme 3, dicyclohexyl borane-catalyzed hydro-borationwith pinacol borane25 proceeded smoothly to generate thevery useful bis-borylated ethylene equivalent 7.5,26 This differen-tially ligated diboron reagent has the capacity for selective cross-coupling of the sp2-hybridized pinacol ester terminus while thesp3-hybridized MIDA boronate remains inert.5,27 Relative to thatpreviously reported,5 the hydroboration of 1 to generate 7 repre-sents a more efficient and practical route to this very usefulbuilding block. As communicated recently,10 1 can also be trans-formed into trans-1-iodo-2-ethenyl MIDA boronate via a one-pothydrostannylation/iododestannylation sequence. We herein dem-onstrate that intermediate, 1-tributylstannyl-2-ethenyl MIDA bor-onate 8, can be isolated in excellent yield. Lynchpin reagents 7 and8 both possess substantial potential for terminus-selective doublefunctionalizations via ICC.
The compatibility of 1 with alkyne reduction was also explored(Scheme 3).28 For example, providing an alternative synthesis ofvinyl MIDA boronate 9,7,8 1 underwent efficient semireduction inthe presence of Lindlar’s catalyst and 1 atm of hydrogen without
O2
Phosess) 5:1
h
MeO NO2
6
2.
Scheme 3.
J.R. Struble et al. / Tetrahedron 66 (2010) 4710e4718 4713
perturbing the MIDA boronate functional group. Alternatively,complete reduction to the corresponding alkane 10 was achievedwith unpoisoned Pd under a H2 pressure of 200 psi. When com-bined with the capacity for Sonogashira coupling described above,this demonstrated compatibility of the MIDA boronate functionalgroup with hydrogenative reduction might prove useful in thepreparation of a range of new alkenyl and alkyl MIDA boronatebuilding blocks.
As a final example, we found that 1 also smoothly undergoesDielseAlder cycloaddition9 with diene 1129 followed by spontane-ous extrusion of carbonmonoxide to generate the pentasubstitutedaryl MIDA boronate 12 (Scheme 3, the structure of 12 was con-firmed via single crystal X-ray analysis). It is notable that the MIDAboronate proved to be stable even when this cycloaddition wasexecuted at 160 �C for 16 h. Collectively, the compatibility of 1withhydroboration, radical-mediated hydrostannylation, hydrogenativereduction, and cycloaddition demonstrate that this MIDA boronatepossesses substantial utility in the synthesis of building blocks forsmall molecule synthesis.
3. Summary and conclusions
Maximally harnessing the building block approach for smallmolecule synthesis requires access to a range of air-stable, highlyversatile, and ideally commercially-available building blocks rep-resenting the substructural elements that most commonly appearin natural products and pharmaceuticals. MIDA boronates repre-sent a very promising platform for this type of synthesis strategy.The results disclosed herein demonstrate that ethynyl MIDA boro-nate 1 can serve as a bifunctional acetylene equivalent for thecontrolled assembly of disubstituted alkynes via ICC. Moreover,executing a range of transformations on the alkyne subunit whileleaving the MIDA boronate functionality intact represents a prom-ising approach for preparing a range of other useful building blocks.Several of the MIDA boronates described herein, including 1, arenow commercially-available.30 Collectively, these findings helpexpand the utility of ICC with MIDA boronates as a versatile
platform for the synthesis of a wide range of pharmaceuticals,natural products, and materials.
4. Experimental
4.1. Materials
Commercial reagents were purchased from SigmaeAldrich,Fisher Scientific, Alfa Aesar, TCI America, or Frontier Scientific,and were used without further purification unless otherwisenoted. Palladium(II) acetate and trans-dichlorobis(triphenyl-phosphine) palladium(II) were purchased from Strem and usedwithout further purification. Copper(I) iodide was purchasedfrom Strem and purified according to Ref. 34. Solvents werepurified via passage through packed columns as described byPangborn and co-workers31 (THF, Et2O, 1,4-dioxane, CH3CN,CH2Cl2/dry neutral alumina; hexane, benzene, and toluene, dryneutral alumina and Q5 reactant; DMSO, DMF/activated molec-ular sieves). All water was deionized prior to use. Triethylaminewas freshly distilled under an atmosphere of nitrogen fromCaH2.
4.2. General experimental procedures
Unless noted, all reactions were performed in flame-driedround-bottom or modified Schlenk flasks fitted with rubber septaunder a positive pressure of argon or in oven-dried (125 �C, >2 h)vials under an atmosphere of argon. Organic solutions were con-centrated via rotary evaporation under reduced pressure witha bath temperature of 40 �C. Reactions were monitored by analyt-ical thin layer chromatography (TLC) performed using the indicatedsolvent on E. Merck silica gel 60 F254 plates (0.25 mm). Compoundswere visualized by exposure to a UV lamp (l¼254 nm), a solution ofKMnO4 or an acidic solution of p-anisaldehyde, followed by briefheating using a Varitemp heat gun. MIDA boronates are compatiblewith standard silica gel chromatography,32 including standardloading techniques.
J.R. Struble et al. / Tetrahedron 66 (2010) 4710e47184714
4.3. Structural analysis
1H NMR spectra were recorded at 20 �C on one of the followinginstruments: Varian Unity 400, Varian Unity 500, Varian UnityInova 500NB. Chemical shifts (d) are reported in parts per million(ppm) downfield from tetramethylsilane and referenced to residualprotium in the NMR solvent (CD2HCN, d¼1.93, center line; acetone-d6 d¼2.04, center line; DMSO-d6, d¼2.05, center line). Data arereported as follows: chemical shift, multiplicity (s¼singlet,d¼doublet, t¼triplet, q¼quartet, quint¼quintet, sext¼sextet,sept¼septet, m¼multiplet, b¼broad, app¼apparent), couplingconstant (J) in Hertz (Hz), and integration. 13C NMR spectra wererecorded on a Varian Unity 500 or 13C NMR spectra for compounds5aem, 6, and 12were recorded at 20 �C on a Varian Unity 600 usinga d1 relaxation time of 20 s. Chemical shifts (d) are reported in partsper million downfield from tetramethylsilane and referenced tocarbon resonances in the NMR solvent (CD3CN, d¼1.30, center line,acetone-d6, d¼29.80, center line, DMSO-d6, d¼39.50, center line).Carbons bearing boron substituents were not observed (quad-rupolar relaxation). High resolution mass spectra (HRMS) wereperformed by Furong Sun and Dr. Steve Mullen at the University ofIllinois School of Chemical Sciences Mass Spectrometry Laboratory.X-ray crystallographic analyses of 1 and 12 were carried out by Dr.Danielle Gray and Amy Fuller at the University of Illinois George L.Clark X-ray facility.
4.4. General procedure A: Sonogashira coupling
In a glove box, a 7-mL vial equipped with a stir-bar wascharged with CuI (10 mol %), PdCl2(PPh3)4 (5 mol %), ethynylMIDA boronate 1 (0.300 mmol, 1.00 equiv), and the aryl halide(0.345 mmol, 1.15 equiv). The vial was sealed with a PTFE-linedseptum screw-cap and removed from the glove box. Undera positive pressure of Ar(g), DMF (1.50 mL), and NEt3 (0.125 mL,8.98 mmol, 2.99 equiv) were added via syringe. The reaction wasallowed to stir at 23 �C for 4e7 h, absorbed onto silica gel usingacetone, loaded onto a silica gel column and purified by flashcolumn chromatography to afford the desired compound. Whennecessary, recrystallization was performed by layering Et2O ontoa concentrated solution of the MIDA boronate in CH2Cl2. Thecrystalline solid was collected by vacuum filtration and washedwith Et2O.
4.5. General procedure B: Sonogashira coupling
In a glove box, a 7-mL vial equipped with a stir-bar wascharged with CuI (10 mol %), PdCl2(PPh3)4 (5 mol %), and ethynylMIDA boronate 1 (0.300 mmol, 1.00 equiv). The vial was sealedwith a PTFE-lined septum screw-cap and removed from the glovebox. Under a positive pressure of Ar(g), the aryl halide(0.345 mmol, 1.15 equiv), DMF (1.50 mL), and NEt3 (0.125 mL,0.898 mmol, 2.99 equiv) were added via syringe. The reactionwas allowed to stir at 23 �C for 4e7 h, absorbed onto silica gelusing acetone, loaded onto a silica gel column and purified byflash column chromatography to afford the desired compound.When necessary, recrystallization was performed by layeringEt2O onto a concentrated solution of the MIDA boronate inCH2Cl2. The crystalline solid was collected by vacuum filtrationand washed with Et2O.
MeN
O
OB
O
ONC
5a
4.5.1. MIDA boronate (5a). Prepared according to general pro-cedure Ausing CuI (6.1 mg, 0.0320 mmol, 0.106 equiv), PdCl2(PPh3)4(11.6 mg, 0.0165 mmol, 0.0546 equiv), ethynyl MIDA boronate 1(54.7 mg, 0.302 mmol, 1.00 equiv), 4-bromobenzonitrile (61.7 mg,0.339 mmol, 1.12 equiv), DMF (1.50 mL), and NEt3 (0.125 mL,0.898 mmol, 2.97 equiv). The reaction was allowed to stir at 23 �Cfor 4 h. Purification via flash chromatography (SiO2; gradient:1:1/3:1 EtOAc/Et2O) afforded 5a as a white crystalline solid(80 mg, 93%).
1H NMR (500 MHz, acetonitrile-d3) d 7.71 (d, J¼8.0 Hz, 2H), 7.62(d, J¼8.0 Hz, 2H), 4.04 (d, J¼17.0 Hz, 2H), 3.92 (d, J¼17.0 Hz, 2H),3.09 (s, 3H). 13C NMR (150 MHz, acetone-d6) d 168.4, 133.3, 133.0,128.5, 118.8, 112.7, 98.6, 62.4, 48.5. HRMS (EIþ) calculated forC14H11BN2O4 (M)þ: 282.0812, found: 282.0804.
MeN
O
OB
O
O
NC
5b
4.5.2. MIDA boronate (5b). Prepared according to general pro-cedure A using CuI (6.4 mg, 0.0336 mmol, 0.114 equiv),PdCl2(PPh3)4 (10.1 mg, 0.0144 mmol, 0.0490 equiv), ethynyl MIDAboronate 1 (53.2 mg, 0.294 mmol, 1.00 equiv), 3-bromobenzonitrile(64.8 mg, 0.356 mmol, 1.21 equiv), DMF (1.50 mL), and NEt3(0.125 mL, 0.898 mmol, 3.05 equiv). The reaction was allowed tostir at 23 �C for 4.5 h. Purification via flash chromatography (SiO2;gradient: 1:1/3:1 EtOAc/Et2O) afforded 5b as a white crystallinesolid (79 mg, 95%).
1H NMR (500 MHz, acetonitrile-d3) d 7.87e7.86 (m, 1H), 7.77 (dt,J¼8.0,1.2 Hz,1H), 7.73 (td, J¼1.2, 8.0 Hz,1H), 7.55e7.52 (m,1H), 4.04(d, J¼17 Hz, 2H), 3.93 (d, J¼17 Hz, 2H), 3.10 (s, 3H). 13C NMR(150 MHz, acetonitrile-d3) d 168.7, 136.9, 136.1, 133.2, 130.6, 124.9,118.9, 113.5, 98.5, 62.5, 48.8. HRMS (EIþ) calculated for C14H11BN2O4(M)þ: 282.0812, found: 282.0815.
MeN
O
OB
O
O
CN
5c
4.5.3. MIDA boronate (5c). Prepared according to general pro-cedure A using CuI (6.1 mg, 0.0320 mmol, 0.108 equiv),PdCl2(PPh3)4 (10.5 mg, 0.0150 mmol, 0.0507 equiv), ethynyl MIDAboronate 1 (53.5 mg, 0.296 mmol, 1.00 equiv), 2-bromobenzonitrile(70.0 mg, 0.384 mmol, 1.30 equiv), DMF (1.50 mL), and NEt3(0.125 mL, 0.898 mmol, 3.05 equiv). The reaction was allowed tostir at 23 �C for 5 h. Purification via flash chromatography (SiO2;gradient: 1:1/3:1 EtOAc/Et2O) afforded 5c as an off-white solid(77 mg, 92%).
1H NMR (500 MHz, acetonitrile-d3) d 7.74 (d, J¼7.5 Hz, 1H),7.68e7.63 (m, 2H), 7.54e7.50 (m, 1H), 4.08 (d, J¼17.0 Hz, 2H), 3.95(d, J¼17.0 Hz, 2H), 3.18 (s, 3H). 13C NMR (150 MHz, acetonitrile-d3)d 168.6, 133.9, 133.8, 133.5, 130.3, 127.0, 118.5, 115.8, 96.8, 62.5, 49.0.HRMS (EIþ) calculated for C14H11BN2O4 (M)þ: 282.0812, found:282.0818.
MeN
O
OB
O
OF3C
5d
J.R. Struble et al. / Tetrahedron 66 (2010) 4710e4718 4715
4.5.4. MIDA boronate (5d). Prepared according to general pro-cedureB using CuI (5.8 mg, 0.0304 mmol, 0.100 equiv), PdCl2(PPh3)4(10.9 mg, 0.0155 mmol, 0.0512 equiv), ethynyl MIDA boronate 1(54.8 mg, 0.303 mmol,1.00 equiv), 4-bromobenzotrifluoride (48 mL,0.348 mmol, 1.15 equiv), DMF (1.50 mL), and NEt3 (0.125 mL,0.898 mmol, 2.96 equiv). The reactionwas allowed to stir at 23 �C for5.5 h. Purification via flash chromatography (SiO2, 1:1 EtOAc/Et2O)followed by recrystallization afforded 5d as awhite crystalline solid(68 mg, 69%).
1H NMR (500 MHz, acetone-d6) d 7.71 (app s, 4H), 4.36(d, J¼17.0 Hz, 2H), 4.20 (d, J¼17.0 Hz, 2H), 3.35 (s, 3H). 13C NMR(150 MHz, acetone-d6) d 168.5,133.2 (t, J¼16 Hz),130.5 (q, J¼32 Hz),128.0, 126.2 (q, J¼4 Hz), 125.0 (q, J¼270 Hz), 98.8, 62.4, 48.5. HRMS(EIþ) calculated for C14H11BF3NO4 (M)þ: 325.0733, found: 325.0748.
MeN
O
OB
O
O
Me
O
5e
4.5.5. MIDA boronate (5e). Preparedaccording togeneral procedureA using CuI (5.9 mg, 0.0310 mmol, 0.102 equiv), PdCl2(PPh3)4(15.5 mg, 0.0192 mmol, 0.0634 equiv), ethynyl MIDA boronate 1(54.9 mg, 0.303 mmol,1.00 equiv), 4-bromoacetophenone (55.0 mg,0.476 mmol, 1.57 equiv), DMF (1.50 mL), and NEt3 (0.125 mL,0.898 mmol, 2.96 equiv). The reactionwas allowed to stir at 23 �C for4 h. Purification via flash chromatography (SiO2, 1:1 EtOAc/Et2O)afforded 5e as a light yellow solid (72 mg, 80%).
1H NMR (500 MHz, DMSO-d6) d 7.96 (d, J¼8.5 Hz, 2H), 7.63(d, J¼8.5 Hz, 2H), 4.33 (d, J¼17.0 Hz, 2H), 4.16 (d, J¼17.0 Hz, 2H),3.09 (s, 3H), 2.58 (s, 3H). 13C NMR (150 MHz, DMSO-d6) d 197.3,168.7, 136.4, 131.8, 128.4, 126.1, 98.5, 61.5, 48.0, 26.8. HRMS (EIþ)calculated for C15H14BNO5 (M)þ: 299.0965, found: 299.0970.
MeN
O
OB
O
OO2N
5f
4.5.6. MIDA boronate (5f). Prepared according to general pro-cedure A using CuI (5.5 mg, 0.0289 mmol, 0.0973 equiv),PdCl2(PPh3)4 (10.3 mg, 0.0147 mmol, 0.0495 equiv), ethynyl MIDAboronate 1 (53.7 mg, 0.297 mmol, 1.00 equiv), 4-bromoacetophe-none (40.7 mg, 0.340 mmol, 1.14 equiv), DMF (1.50 mL), and NEt3(0.125 mL, 0.898 mmol, 3.02 equiv). The reaction was allowed tostir at 23 �C for 4 h. Purification via flash chromatography (SiO2;gradient: 1:1/3:1 EtOAc/Et2O) followed by recrystallizationafforded 5f as an orange crystalline solid (58 mg, 65%).
1H NMR (500 MHz, DMSO-d6) d 8.23 (d, J¼8.5 Hz, 2H), 7.76(d, J¼9.0 Hz, 2H), 4.35 (d, J¼17.0 Hz, 2H), 4.17 (d, J¼17.0 Hz, 2H), 3.11(s, 3H). 13C NMR (150 MHz, DMSO-d6) d 168.7, 147.0, 132.8, 129.1,123.8, 97.4, 61.6, 48.0. HRMS (EIþ) calculated for C13H11BN2O6 (M)þ:302.0710, found: 302.0706.
MeN
O
OB
O
OMe
O2N 5g
4.5.7. MIDA boronate (5g). Prepared according to general pro-cedureAusing CuI (6.2 mg, 0.0325 mmol, 0.102 equiv), PdCl2(PPh3)4(10.9 mg, 0.0155 mmol, 0.0489 equiv), ethynyl MIDA boronate 1
(57.3 mg, 0.317 mmol, 1.00 equiv), 4-bromo-2-nitrotoluene(86.5 mg, 0.400 mmol, 1.26 equiv), DMF (1.50 mL), and NEt3(0.125 mL, 0.898 mmol, 2.83 equiv). The reactionwas allowed to stirat 23 �C for 6 h. Purification via flash chromatography (SiO2, 1:1EtOAc/Et2O) followed by recrystallization afforded 5g as an orangecrystalline solid (72 mg, 72%).
1H NMR (500 MHz, DMSO-d6) d 8.08 (d, J¼1.0 Hz, 1H), 7.73(dd, J¼8.0, 1.5 Hz, 1H), 7.53 (d, J¼8.0 Hz, 1H), 4.33 (d, J¼17.0 Hz, 2H),4.15 (d, J¼17.0 Hz, 2H), 3.08 (s, 3H), 2.51 (s, 3H). 13C NMR (150 MHz,DMSO-d6) d 168.7, 148.9, 135.8, 133.4, 133.2, 127.1, 121.3, 96.9, 61.5,47.9, 19.4. HRMS (EIþ) calculated for C14H13BN2O6 (M)þ: 316.0867,found: 316.0862.
MeN
O
OB
O
OMeO
5h
4.5.8. MIDA boronate (5h). Prepared according to general pro-cedure A using CuI (5.7 mg, 0.0299 mmol, 0.100 equiv),PdCl2(PPh3)4 (10.2 mg, 0.0145 mmol, 0.0486 equiv), ethynyl MIDAboronate 1 (54.0 mg, 0.298 mmol, 1.00 equiv), 4-iodoanisole(81.7 mg, 0.349 mmol, 1.17 equiv), DMF (1.50 mL), and NEt3(0.125 mL, 0.898 mmol, 3.01 equiv). The reaction was allowed tostir at 23 �C for 6.5 h. Purification via flash chromatography (SiO2,1:1 EtOAc/Et2O) followed by recrystallization afforded 5h as a tancrystalline solid (69 mg, 80%).
1H NMR (500 MHz, acetonitrile-d3) d 7.54 (d, J¼8.5 Hz, 2H), 7.01(d, J¼8.5 Hz, 2H), 4.14 (d, J¼17.0 Hz, 2H), 4.02 (d, J¼17.0 Hz, 2H),3.90 (s, 3H), 3.19 (s, 3H). 13C NMR (150 MHz, acetonitrile-d3) d 168.8,161.0, 134.2, 115.5, 115.0, 101.1, 62.4, 56.0, 48.7. HRMS (ESIþ) calcu-lated for C14H15BNO5 (MþH)þ: 288.1043, found: 288.1043.
MeN
O
OB
O
OMe
5i
4.5.9. MIDA boronate (5i). Prepared according to general pro-cedure a using CuI (5.2 mg, 0.0273 mmol, 0.0872 equiv),PdCl2(PPh3)4 (10.8 mg, 0.0154 mmol, 0.0492 equiv), ethynyl MIDAboronate 1 (56.7 mg, 0.313 mmol, 1.00 equiv), 4-iodotoluene(76.1 mg, 0.349 mmol, 1.12 equiv), DMF (1.50 mL), and NEt3(0.125 mL, 0.898 mmol, 2.86 equiv). The reaction was allowed tostir at 23 �C for 4.5 h. Purification via flash chromatography (SiO2,1:1 EtOAc/Et2O) followed by recrystallization afforded 5i as whitecrystalline solid (64 mg, 75%).
1H NMR (500 MHz, acetone-d6) d 7.37 (d, J¼8.0 Hz, 2H), 7.18(d, J¼8.0 Hz, 2H), 4.32 (d, J¼17.0 Hz, 2H), 4.16 (d, J¼17.0 Hz, 2H),3.30 (s, 3H), 2.33 (s, 3H). 13C NMR (150 MHz, acetone-d6) d 168.6,139.6, 132.4, 129.9, 120.9, 100.7, 62.2, 48.4, 21.3. HRMS (EIþ) calcu-lated for C14H14BNO4 (M)þ: 271.1016, found: 271.1005.
MeN
O
OB
O
O
Me
5j
4.5.10. MIDA boronate (5j). Prepared according to general pro-cedure B using CuI (5.5 mg, 0.0289 mmol, 0.0941 equiv),PdCl2(PPh3)4 (11.1 mg, 0.0158 mmol, 0.0515 equiv), ethynyl MIDAboronate 1 (55.5 mg, 0.307 mmol, 1.00 equiv), 2-iodotoluene
J.R. Struble et al. / Tetrahedron 66 (2010) 4710e47184716
(45 mL, 0.354 mmol, 1.15 equiv), DMF (1.50 mL), and NEt3 (0.125 mL,0.898 mmol, 2.92 equiv). The reaction was allowed to stir at 23 �Cfor 5.5 h. Purification via flash chromatography (SiO2, 1:1 EtOAc/Et2O) afforded 5j as a white crystalline solid (73 mg, 88%).
1H NMR (500 MHz, acetone-d6) d 7.44 (d, J¼8.0 Hz, 1H),7.27e7.24 (m, 2H), 7.19e7.17 (m, 1H), 4.34 (d, J¼17.0 Hz, 2H), 4.19(d, J¼17.0 Hz, 2H), 3.34 (s, 3H), 2.42 (s, 3H). 13C NMR (150 MHz,acetone-d6) d 168.6, 140.9, 132.8, 130.2, 129.5, 126.4, 123.6, 99.3,62.3, 48.5, 20.8. HRMS (EIþ) calculated for C14H14BNO4 (M)þ:271.1016, found: 271.1020.
MeN
O
OB
O
O
MeO
5k
4.5.11. MIDA boronate (5k). Prepared according to general pro-cedure B using CuI (6.4 mg, 0.0336 mmol, 0.110 equiv),PdCl2(PPh3)4 (10.7 mg, 0.0152 mmol, 0.0508 equiv), ethynyl MIDAboronate 1 (55.2 mg, 0.305 mmol, 1.00 equiv), 3-iodoanisole (42 mL,0.353 mmol, 1.16 equiv), DMF (1.50 mL), and NEt3 (0.125 mL,0.898 mmol, 2.94 equiv). The reaction was allowed to stir at 23 �Cfor 7 h. Purification via flash chromatography (SiO2,1:1 EtOAc/Et2O)afforded 5k as a white crystalline solid (69 mg, 90%).
1H NMR (500 MHz, acetone-d6) d 7.27 (app t, J¼8.0 Hz, 1H),7.07e7.03 (m, 2H), 6.95 (ddd, J¼8.5, 2.5, 1.0 Hz, 1H), 4.33(d, J¼17.0 Hz, 2H), 4.18 (d, J¼17.0 Hz, 2H), 3.80 (s, 3H), 3.31 (s, 3H).13CNMR (150 MHz, acetone-d6) d 168.5, 160.3, 130.4, 130.3, 124.8, 117.3,115.8, 100.5, 62.3, 55.5, 48.4. HRMS (EIþ) calculated for C14H14BNO5(M)þ: 287.0965, found: 287.0953.
MeN
O
OB
O
O
S
5l
4.5.12. MIDA boronate (5l). Prepared according to general pro-cedure B using CuI (6.0 mg, 0.0315 mmol, 0.107 equiv),PdCl2(PPh3)4 (11.4 mg, 0.0162 mmol, 0.0549 equiv), ethynyl MIDAboronate 1 (53.4 mg, 0.295 mmol, 1.00 equiv), 2-bromothiazole(35 mL, 0.362 mmol,1.23 equiv), DMF (1.50 mL), and NEt3 (0.125 mL,0.898 mmol, 3.04 equiv). The reaction was allowed to stir at 23 �Cfor 6 h. Purification via flash chromatography (SiO2, EtOAc) fol-lowed by recrystallization afforded 5l as a light-yellow crystallinesolid (52 mg, 67%).
1H NMR (500 MHz, acetone-d6) d 7.38 (dd, J¼5.0, 1.0 Hz,1H), 7.19(dd, J¼3.8, 1.0 Hz, 1H), 6.94 (dd, J¼5.0, 3.8 Hz, 1H), 4.22(d, J¼17.0 Hz, 2H), 4.08 (d, J¼17.0 Hz, 2H), 3.18 (s, 3H). 13C NMR(150 MHz, acetone-d6) d 168.5, 133.6, 128.7, 128.0, 123.6, 93.1, 62.4,48.4. HRMS (EIþ) calculated for C11H10BNO4S (M)þ: 263.0424,found: 263.0441.
MeN
O
OB
O
O
N
5m
4.5.13. MIDA boronate (5m). Prepared according to general pro-cedure B using CuI (6.0 mg, 0.0315 mmol, 0.100 equiv),PdCl2(PPh3)4 (10.6 mg, 0.0151 mmol, 0.0479 equiv), ethynyl MIDAboronate 1 (57.0 mg, 0.315 mmol, 1.00 equiv), 2-bromopyridine
(34 mL, 0.349 mmol, 1.11 equiv), DMF (1.50 mL), and NEt3 (0.125 mL,0.898 mmol, 2.85 equiv). The reaction was allowed to stir at 23 �Cfor 6 h. Purification via flash chromatography (SiO2, 3:2 Et2O:CH3CN) followed by recrystallization afforded 5m as a pale-greencrystalline solid (45 mg, 55%).
1H NMR (500 MHz, acetonitrile-d3) d 8.58 (br s, 1H), 7.75 (dt,J¼8.0, 1.5 Hz, 1H), 7.54 (d, J¼3.8, 1.0 Hz, 1H), 7.35e7.33 (m, 1H), 4.33(d, J¼17.0 Hz, 2H), 4.18 (d, J¼17.0 Hz, 2H), 3.12 (s, 3H). 13C NMR(150 MHz, DMSO-d6) d 168.7, 150.0, 142.1, 136.7, 127.6, 123.9, 98.9,61.6, 48.0. HRMS (ESIþ) calculated for C12H12BN2O4 (MþH)þ:259.0890, found: 259.0885.
NO2
MeO
6
4.5.14. 1-Methoxy-4-((4-nitrophenyl)ethynyl)benzene (6). Underambient atmosphere a 40-mL vial was equipped with a magneticstir-bar and charged with Pd(OAc)2 (2.8 mg, 0.0125 mmol,0.050 equiv), SPhos (10.5 mg, 0.0256 mmol, 0.100 equiv), 1-bromo-4-nitrobenzene (50.3 mg, 0.249 mmol, 1.00 equiv), and MIDA bor-onate 5j (76.8 mg, 0.300 mmol, 1.20 equiv).The vial was sealed witha PTFE-lined septum screw-cap and placed under an atmosphere ofAr(g). To the vial was added 1,4-dioxane (9.0 mL) via syringe andthe resulting mixture stirred for 10 min at 23 �C. To the vial wasadded aq K3PO4 (degassed by spargingwith Ar(g) for 45 min; 3.0 M,1.8 mL, 5.4 mmol, 21.6 equiv). The vial was placed in a 60 �C oil bathwith stirring for 6 h. The mixture was allowed to cool to 23 �C,transferred to a separatory funnel and diluted with aq NaOH (1.0 M,8 mL). The mixture was extracted with Et2O (3�10 mL). The com-bined organic fractions werewashed with brine (15 mL), dried overNa2SO4, filtered, and concentrated in vacuo. The crude orangeresidue was purified via flash chromatography (SiO2; gradient:100:0/19:1 hexanes/EtOAc) to provide 6 as a bright yellow crys-talline solid (54 mg, 86%).
1H NMR (500 MHz, acetone-d6) d 8.25 (d, J¼9.0 Hz, 2H), 7.75(d, J¼9.0 Hz, 2H), 7.54 (d, J¼9.0 Hz, 2H), 7.00 (d, J¼9.0 Hz, 2H), 3.85(s, 3H). 13C NMR (150 MHz, acetone-d6) d 161.5, 147.7, 134.2, 132.9,131.2, 124.5, 115.2, 114.7, 95.5, 87.2, 55.7. HRMS (EIþ) calculated forC15H11NO3 (M)þ: 253.0739, found: 253.0744.
MeN
O
OB
O
O
B
7
O
O
Me
Me
Me
Me
4.5.15. MIDA boronate (7)5. To a 40-mL flame-dried vial equippedwith a magnetic stir-bar was added ethynyl MIDA boronate 1(500 mg, 2.8 mmol, 1.0 equiv). The vial was taken into a glove boxwhere soliddicyclohexylborane33 (98 mg,0.55 mmol, 20 mol %)wasadded. The vial was capped with a PTFE-lined septa cap, removedfrom the glove box, and placed under N2. To the vial was added THF(5.5 mL, 0.50 M) and neat pinacolborane (480 mL, 3.3 mmol,1.2 equiv). The vial was sealed under N2 and placed in an 85 �Cheating block. The solution turned clear, colorless within 20 min.After stirring at 85 �C for 17 h, the crude reaction solution wasconcentrated in vacuo. The resulting solidwasdry loadedontoCelitefrom an acetone solution and purified via flash chromatography
J.R. Struble et al. / Tetrahedron 66 (2010) 4710e4718 4717
(SiO2; gradient: 100:0/2:1 Et2O/acetone) to afford bisborylatedMIDA boronate 7 as a white solid (717 mg, 84%).
MeN
O
OB
O
O
Bu3Sn
8
4.5.16. MIDA boronate (8). A dry 25-mL Schlenk flask equippedwith amagnetic stir-bar was chargedwith ethynylMIDA boronate 1(182 mg, 1.0 mmol, 1.0 equiv) and 2,20-azobis(2-methylpropioni-trile) (16 mg, 0.10 mmol, 1.0 equiv) and was then placed under N2
atm. To the flask was added THF (5.0 mL) followed by HSnBu3(0.40 mL, 1.5 mmol, 1.5 equiv). The flask was fitted with a refluxcondenser vented to N2 atmosphere. The solution was heated to65 �C internal temp (70 �C oil bath) with stirring for 18 h. Thesolutionwas allowed to cool to 23 �C andwas transferred to a 60-mLseparatory funnel using Et2O (15 mL). The solutionwaswashedwithaq 1 M HCl (10 mL), satd aq NaHCO3 (10 mL), and brine (5 mL). Thesolution was dried over MgSO4, filtered, and concentrated in vacuoto afford a colorless oil that was purified via flash chromatography(SiO2; gradient: 100:0/5:1 Et2O:MeCN) to afford the title com-pound as a colorless solid (441 mg, 93%).
1H NMR (500 MHz, acetone-d6) d 6.99 (app sext, J¼22.0 Hz, 1H),6.43 (app sext, J¼22.0 Hz, 1H), 4.19 (d, J¼17.0 Hz, 2H), 3.97(d, J¼17.0 Hz, 2H), 2.98 (s, 3H), 1.55 (m, 6H), 1.33 (app sext, J¼7.5 Hz,6H), 0.94 (t, J¼7.5 Hz, 6H), 0.89 (t, J¼7.5 Hz, 9H). 13C NMR (125 MHz,acetone-d6) d 169.2, 147.6, 62.3, 47.5, 29.9 (app hept), 27.9 (t), 14.0,9.8 (t). HRMS (ESIþ) calculated for C19H37BNO4Sn (MþH)þ:474.1855, found: 474.1838.
MeN
O
OB
O
O
9
4.5.17. Ethenyl MIDA boronate (9)7. An oven-dried 7-mL vialequipped with a magnetic stir-bar was charged with ethynyl MIDAboronate 1 (45 mg, 0.25 mmol, 1.0 equiv), Lindlar’s cat. (2.5 mg),and 1,4-dioxane (1.5 mL). Quinoline (0.015 mL, 0.125 mmol,0.50 equiv) was added and the vial sealed with a PTFE-lined plasticscrew-cap. The vial was filled with hydrogen gas using a balloonand the reaction mixture was stirred at 23 �C for 3.5 h. The reactionmixture was diluted with acetonitrile (1.0 mL) and filtered throughCelite �. The crude product was purified via flash chromatography(SiO2, 19:1 EtOAc/MeCN) to afford 9 as a colorless crystalline solid(37 mg, 81%).
MeN
O
OB
O
OMe
10
4.5.18. Ethyl MIDA boronate (10). An oven-dried 7-mL vial equip-ped with a magnetic stir-bar was charged with ethynyl MIDA bor-onate 1 (45 mg, 0.25 mmol, 1.0 equiv), Lindlar’s cat. (5.0 mg), and1,4-dioxane (1.0 mL). The vial containing this reaction mixture wasplaced in a hydrogenation bomb and the hydrogen pressure wasadjusted to 200 psi. The reaction mixture was allowed to stir at23 �C for 15 h. The reaction mixture was diluted with acetonitrile
(1.0 mL) and filtered through Celite�. The resulting colorless solu-tion was concentrated in vacuo to provide 10 as a colorless crys-talline solid (43 mg, 93%).
1H NMR (500 MHz, acetonitrile-d3) d 3.92 (d, J¼16.5 Hz, 2H),3.76 (d, J¼16.5 Hz, 2H), 2.84 (s, 3H), 0.89 (t, J¼8.0 Hz, 3H), 0.58(q, J¼8.0 Hz, 2H). 13C NMR (100 MHz, acetonitrile-d3) d 169.1, 62.6,46.3, 8.0. HRMS (ESIþ) calculated for C7H13BNO4 (MþH)þ: 186.0938,found: 186.0946.
MeN
O
OB
O
O
MeO2C
CO2Me
Ph
Ph H
12
4.5.19. MIDA boronate (12). A 5-mL round-bottom flask wasequipped with a magnetic stir-bar and charged with ethynyl MIDAboronate 1 (172 mg, 0.950 mmol, 1.00 equiv), dimethyl 2-oxo-4,5-diphenylcyclopenta-3,5-diene-1,3-dicarboxylate 11 (460 mg,1.32 mmol, 1.40 equiv), and mesitylene (1.0 mL). The flask wasequipped with a water-jacketed reflux condensor and an Ar(g)inlet. The reaction was allowed to stir in a 160 �C oil bath for 16 h.The black reaction mixture was allowed to cool to 23 �C, absorbedonto silica gel using acetone, and semi-purified via flash chroma-tography (SiO2, 5:4 EtOAc/Et2O). The semi-purified brown powderwas dissolved in a minimal volume of acetone and then pre-cipitated by the addition of Et2O with vigorous stirring. Collectionby vacuum filtration and washing with Et2O afforded 12 as a whitepowder (269 mg, 56%).
1H NMR (500 MHz, acetone-d6) d 8.00 (s, 1H), 7.14e7.12 (m, 6H),7.00e6.99 (m, 4H), 4.43 (d, J¼17.5 Hz, 2H), 4.25 (d, J¼17.5 Hz, 2H),3.48 (s, 3H), 3.30 (s, 3H), 3.11 (s, 3H). 13C NMR (150 MHz, acetone-d6) d 172.6, 169.4, 169.3, 142.2, 142.1, 139.9, 139.7, 139.1, 134.3, 134.1,131.0, 130.4, 128.0, 127.9, 127.6, 127.4, 64.7, 52.4, 52.1, 50.2. HRMS(EIþ) calculated for C27H24BNO8 (M)þ: 501.1595, found: 501.1586.
Acknowledgements
We gratefully acknowledge E.M. Woerly and E.P. Gillis for per-forming the synthesis of 7 and 8, respectively. We also thank theNSF (CAREER 0747778), Howard Hughes Medical Institute, theArnold and Mabel Beckman Foundation, and Bristol-Myers Squibbfor financial support, Dr. Danielle Gray and Amy Fuller for X-raycrystallographic analysis, and Dr. Steve Mullen and Furong Sun formass spectral analysis. M.D.B. is a Howard HughesMedical InstituteEarly Career Scientist, Beckman Young Investigator, Sloan Founda-tion Research Fellow, Dreyfus New Faculty Awardee, Bristol-MyersSquibb Unrestricted Grant in Synthetic Organic ChemistryAwardee, Eli Lilly Grantee, Amgen Young Investigator, and Astra-Zeneca Excellence in Chemistry Awardee.
Supplementary data
Supplementary data associated with this article can be found inthe online version at doi:10.1016/j.tet.2010.04.020.
References and notes
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